Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

Rcom-H'cheo-Gauthier, Alexandre Nay; Osborne, Samantha; Meedeniya, Adrian Cuda Banda; Pountney, Dean L.

doi:10.3389/fnins.2016.00570

Cited by 36 publications

(35 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, Trimethadione (TMO), a Ca 2+ channel blocker with broad selectivity commonly used as an anti-epileptic drug, blocked K + -depolarization induced Ca 2+ influx into SH-SY5Y cells resulting in loss of α-syn positive aggregate formation post-depolarization [ 81 ]. Furthermore, recent studies using a unilateral rotenone (oxidative stress) lesion mouse model of PD (described in [ 85 ]), also showed improved survival of CB+ neurons and almost exclusive partitioning of α-syn aggregates in the CB− cell population ( Figure 3 ; [ 86 ]). In this model, injection of rotenone into the medial forebrain bundle of one brain hemisphere only, allows for comparison of α-syn inclusion body positive and CB+ neurons between treated and untreated hemispheres.…”

Section: Increased Intracellular Ca 2+ Induces mentioning

confidence: 92%

“… Unilateral rotenone lesion mouse (oxidative stress) model of PD shows α-syn aggregates primarily in calbindin-negative neurons. ( A ) CB+ neurons (arrowheads) showed relative protection in the unilateral rotenone lesion (oxidative stress) model of PD (as detailed in [ 85 ]), with more CB+ neurons surviving in the treated than in the untreated hemisphere and partitioning of α-syn aggregates (arrow) in the CB− neurons [ 86 ]. Scale bar, 50 μm.…”

Section: Increased Intracellular Ca 2+ Induces mentioning

confidence: 99%

See 1 more Smart Citation

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

2014

View full text Add to dashboard Cite

In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity.

show abstract

Section: Increased Intracellular Ca 2+ Induces mentioning

confidence: 92%

Section: Increased Intracellular Ca 2+ Induces mentioning

confidence: 99%

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

2014

View full text Add to dashboard Cite

show abstract

“…Studies on alpha-synuclein knockout mice implicate its role in neurotransmitter regulation (Yavich et al, 2004). The protein may also act as a calcium channel activator and mediator of calcium entry and may increase cell toxicity from oxidative stress (Dryanovski et al, 2013; Rcom-H'cheo-Gauthier et al, 2016). …”

Section: Lewy Bodies and Alpha-synucleinmentioning

confidence: 99%

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

et al. 2017

Self Cite

View full text Add to dashboard Cite

Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies. In PD, total tissue copper is decreased, including neuromelanin-bound copper and there is a reduction in copper transporter CTR-1. Conversely cerebrospinal fluid (CSF) copper is increased. MT-1/2 expression is increased in activated astrocytes in alpha-synucleinopathies, yet expression of the neuronal MT-3 isoform may be reduced. MTs have been implicated in inflammatory states to perform one-way exchange of copper, releasing free zinc and recent studies have found copper bound to alpha-synuclein is transferred to the MT-3 isoform in vitro and MT-3 is found bound to pathological alpha-synuclein aggregates in the alpha-synucleinopathy, multiple systems atrophy. Moreover, both MT and alpha-synuclein can be released and taken up by neural cells via specific receptors and so may interact both intra- and extra-cellularly. Here, we critically review the role of MTs in copper dyshomeostasis and alpha-synuclein aggregation, and their potential as biomarkers and therapeutic targets.

show abstract

“…The cellular dysfunctions underlying these pathological hallmarks include abnormal mitochondrial metabolism, oxidative stress, neuroinflammation and upregulation of unfolded protein response (UPR) in the endoplasmic reticulum (ER) 11 , 12 . One of the most important signaling molecules, and a common denominator in these cellular dysfunctions, is intracellular calcium [Ca 2+ ] i 13 , 14 . Ca 2+ levels are tightly controlled throughout neurons, including within major organelles such as mitochondria and ER.…”

Section: Introductionmentioning

confidence: 99%

MPP+ decreases store-operated calcium entry and TRPC1 expression in Mesenchymal Stem Cell derived dopaminergic neurons

Sun

Selvaraj

Pandey

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Parkinson’s disease is a neurodegenerative disorder involving the progressive loss of dopaminergic neurons (DNs), with currently available therapeutics, such as L-Dopa, only able to relieve some symptoms. Stem cell replacement is an attractive therapeutic option for PD patients, and DNs derived by differentiating patient specific stem cells under defined in-vitro conditions may present a viable opportunity to replace dying neurons. We adopted a previously published approach to differentiate Mesenchymal Stem Cells (MSCs) into DN using a 12-day protocol involving FGF-2, bFGF, SHH ligand and BDNF. While MSC-derived DNs have been characterized for neuronal markers and electrophysiological properties, we investigated store-operated calcium entry (SOCE) mechanisms of these DNs under normal conditions, and upon exposure to environmental neurotoxin, 1-methyl, 4-phenyl pyridinium ion (MPP+). Overall, we show that MSC-derived DNs are functional with regard to SOCE mechanisms, and MPP+ exposure dysregulates calcium signaling, making them vulnerable to neurodegeneration. Since in-vitro differentiation of MSCs into DNs is an important vehicle for PD disease modeling and regenerative medicine, the results of this study may help with understanding of the pathological mechanisms underlying PD.

show abstract

Calcium: Alpha-Synuclein Interactions in Alpha-Synucleinopathies

Cited by 36 publications

References 94 publications

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

MPP+ decreases store-operated calcium entry and TRPC1 expression in Mesenchymal Stem Cell derived dopaminergic neurons

Contact Info

Product

Resources

About